Insulin action in brain regulates systemic metabolism and brain function

Abstract

Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.

Figure 1

Expression of IR, IGF-1R, IRS-1, and IRS-2 in the brain. The expressions of IR, IGF-1R, IRS-1, and IRS-2 were determined by quantitative real-time PCR of brain regions dissected from male C57BL/6 mice. Serial dilutions of plasmids encoding the cDNA sequences of corresponding genes were used for the standard curves. Data are expressed as the copy number per nanograms of RNA transcribed. Cb, cerebellum; CP, caudate putamen; Hpc, hippocampus; Hy, hypothalamus; NA, nucleus accumbens; NST, nucleus tractus solitaries; PFC, prefrontal cortex; RN, raphe nucleus; VTA, ventral tegmental area.

Figure 2

Insulin regulates orexigenic and anorexigenic peptides and body temperature. A: Insulin regulates appetite through the hypothalamus. In the arcuate nucleus (ARC) of the hypothalamus, insulin binds to IRs on POMC neurons to increase the expression of anorexigenic peptides, POMC, and CaRT, which results in increased activity of α-melanocyte–stimulating hormone (α-MSH) on melanin-concentrating hormone (MCH) neurons in the paraventricular nucleus (PVN). Conversely, insulin acts on AgRP neurons to inhibit the expression of orexigenic peptides AgRP and NPY. In addition, upon insulin binding, IR activates PI3K, triggering ATP-dependent potassium (K_ATP) channels, K⁺ efflux, and hyperpolarization of AgRP neurons. This results in the attenuation of the inhibitory effect of AgRP neurons on both MCH and POMC neurons. In parallel, insulin and leptin act to decrease food intake. B: Transcription of the orexigenic peptides AgRP and NPY is increased, and transcription of the anorexigenic peptides POMC and CaRT is decreased in the hypothalami of STZ-treated mice compared with controls, as determined by microarray analysis on isolated hypothalami of C57BL/6 mice 10 days after treatment with vehicle or STZ to induce diabetes. Data are expressed as the percentage change over vehicle-treated mice. P < 0.01 for all genes. C: Brain IR knockout (NIRKO) mice show a significant drop in body temperature compared with controls when exposed to 4°C cold stress, indicating a defect in thermogenesis. Experiments were performed on 17-month-old female mice. ***P < 0.001.

Figure 3

Effects of insulin signaling in the brain on central and peripheral function. Brain insulin resistance results in increased food intake, hypothalamic hypogonadism, hypothermia, decreased white fat mass, increased hepatic glucose output, impaired response to hypoglycemia, and impaired neural function. ARC, arcuate nucleus; DMX, dorsal motor vagal nucleus; NTS, nucleus of the solitary tract.

Figure 4

Insulin resistance in the brain influences neurological function through multiple pathways. Impaired insulin signaling in the brain leads to decreased SREBP-2/SCAP-dependent cholesterol synthesis, altered synaptic plasticity, mitochondrial dysfunction, and increased tau phosphorylation, all of which may contribute downstream to impaired neurological functioning, including AD and mood disorders. AMPA-R, AMPA receptor; NMDA-R, NMDA receptor.

Figure 5

SCAP and SREBP-2 are important for synapse formation, nerve firing, and memory tasks. Top: SREBP-2 was silenced with a green fluorescent protein (GFP)-lentiviral construct (Lenti-shSREBP-2 [short hairpin SREBP-2]) in primary cultured mouse hippocampal cells. The PSD95 marker is represented in red, and the neuronal marker MAP2 is shown in blue. Adapted from Suzuki et al. (61). Middle: Mice with heterozygous deletion of SCAP show a decrease in spontaneous neuronal activity, as determined by basal recordings of miniature excitatory postsynaptic current in area CA1 neurons (adapted from Suzuki et al. [99]). Bottom: Impaired memory task performance. For the novel object recognition test, mice were trained for 5 min with two identical objects. One hour later, they were placed back in the same cage with one familiar and one novel object, and were monitored by video for 5 min. Mice with a heterozygous deletion of SCAP in the brain showed no exploratory preference for the novel object. Adapted from Suzuki et al. (99). CTR, control.